EP2496249B1 - Glp-1 receptor agonist for use in treating obstructive sleep apnea - Google Patents

Glp-1 receptor agonist for use in treating obstructive sleep apnea Download PDF

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Publication number
EP2496249B1
EP2496249B1 EP10828932.3A EP10828932A EP2496249B1 EP 2496249 B1 EP2496249 B1 EP 2496249B1 EP 10828932 A EP10828932 A EP 10828932A EP 2496249 B1 EP2496249 B1 EP 2496249B1
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EP
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Prior art keywords
seq
exendin
glp
lys
glu
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EP10828932.3A
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German (de)
French (fr)
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EP2496249A2 (en
EP2496249A4 (en
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Eve Van Cauter
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Amylin Pharmaceuticals LLC
Eli Lilly and Co
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Amylin Pharmaceuticals LLC
Eli Lilly and Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons

Definitions

  • the description is directed to the field of medicine, more particularly, to sleep.
  • Obstructive sleep apnea is caused by a blockage of the airway, which usually occurs when the soft tissue in the throat collapses and closes during sleep.
  • the blockage can occur in a portion of the pharyngeal lumen and may include obstructions formed by the collapse of the tongue against the posterior wall of the pharynx, the collapse of the lateral pharyngeal walls, and the combined collapse of the tongue with impingement of the soft palate, particularly the posterior portion of the soft palate including the uvula.
  • the brain briefly arouses the sufferer in order to initiate the resumption of breathing. This type of sleep, however, is extremely fragmented and of poor quality.
  • obstructive sleep apnea affects more than twelve million Americans. Obstructive sleep apnea may result in high blood pressure, cardiovascular disease, weight gain, impotency, headaches, and memory problems if it is not treated. Despite the seriousness of obstructive sleep apnea, a general lack of awareness among the public and healthcare professionals results in the vast majority of obstructive sleep apnea sufferers remaining undiagnosed and untreated.
  • obstructive sleep apnea in patients in need thereof by administering to the patients therapeutically effective amounts of GLP-1 receptor agonist compounds to treat obstructive sleep apnea.
  • the treatment of obstructive sleep apnea includes treatment for reducing the severity of obstructive sleep apnea.
  • obstructive sleep apnea may be treated by administering BYETTA® (exenatide; Amylin Pharmaceuticals, Inc., San Diego, CA, and Eli Lilly and Co., Indianapolis, IN) to the patient.
  • BYETTA® is a pharmaceutical composition that generally comprises a GLP-1 receptor agonist compound (e.g., exenatide), a preservative (e.g., metacresol), a tonicity-adjusting agent (e.g., mannitol), and a buffer (e.g., an acetate buffer).
  • obstructive sleep apnea may be treated by administering BYDUREONTM or exenatide once weekly (EQW) (Amylin Pharmaceuticals, Inc., Eli Lilly and Company, Alkermes, Inc.) to the patient.
  • Exenatide once weekly is a pharmaceutical composition that comprises biodegradable microspheres (e.g., poly(lactide-co-glycolide) microspheres) and exenatide.
  • Exenatide once weekly is described, for example, in WO 2007/024700 .
  • the patient may be a mammal, such as a human.
  • Conditions such as obstructive sleep apnea are usually more common in diabetic and/or obese patients, such that the patient being treatedis more likely to be diabetic, obese, or diabetic and obese.
  • the description relates to GLP-1 receptor agonist compounds as defined in the claims for use to treat obstructive sleep apnea in patients in need thereof.
  • the GLP-1 receptor agonist compounds are administered to patients in therapeutically effective amounts.
  • the patient may be a mammal, such as a human.
  • the description relates to pharmaceutical compositions comprising GLP-1 receptor agonist compounds for use to treat obstructive sleep apnea in patients in need thereof.
  • the pharmaceutical compositions comprise therapeutically effective amounts of the GLP-1 receptor agonist compounds.
  • the compositions may be immediate release (e.g., administered qid, bid, tid) or extended release (e.g., administered QW or once a month).
  • the patient may be a mammal, such as a human.
  • the description relates to GLP-1 receptor agonist compounds to treat obstructive sleep apnea by administering therapeutically effective amounts to patients in need thereof.
  • a patient with obstructive sleep apnea stops breathing numerous times, for varying amounts of time, during sleep.
  • Methods for treating obstructive sleep apnea include reducing the number of times a patient stops breathing during the night and/or reducing the length of time a patient stops breathing. "Reducing" includes eliminating the symptoms of obstructive sleep apnea.
  • the present invention provides a GLP-1 receptor agonist compound or a pharmaceutical composition comprising the GLP-1 receptor agonist compound for use in the treatment of obstructive sleep apnea in a patient in need thereof, said treatment comprising peripherally administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition to treat the obstructive sleep apnea, wherein the GLP-1 receptor agonist compound is a GLP-1(7-37) analog ("GLP1(7-37)" disclosed as SEQ ID NO: 22); exendin-4 (SEQ ID NO:1); exendin-3 (SEQ ID NO:2); Leu 14 -exendin-4 (SEQ ID NO:3); Leu 14 ,Phe 25 -exendin-4 (SEQ ID NO:4); Leu 14 ,Ala 19 ,Phe 25 -exendin-4 (SEQ ID NO:5); exendin-4(1-30) (SEQ ID NO:6); Leu 14 -exendin-4(1-30) (
  • Obstructive sleep apnea may be classified by the Apnea-Hypopnea Index (AH1) which measures the total number of episodes of apnea and hypopnea occurring during sleep divided by the hours of sleep time.
  • the AHI classifies sleep apnea as normal (i.e., less than 5 pauses in breathing lasting more than 10 seconds): mild (i.e., 5-15 pauses in breathing lasting more than 10 seconds); moderate (i.e., 15-30 pauses in breathing lasting more than 10 second); or severe (i.e., more than 30 pauses in breathing lasting more than 10 seconds).
  • the treatment of sleep apnea described herein includes reducing the severity of obstructive sleep apnea based on the AHI.
  • the invention described herein reduces the patient's AHI from severe to moderate; or from severe to mild; or from severe to normal.
  • the invention described herein reduces the patient's AHI from moderate to mild, or from moderate to normal.
  • the methods described herein reduce the patient's AHI from mild to normal.
  • GLP-1 receptor agonist compound refers to compounds having GLP-1 receptor activity. Such compounds are exendins, exendin analogs, and GLP-1(7-37) analogs.
  • exendin includes naturally occurring (or synthetic versions of naturally occurring) exendin peptides that are found in the salivary secretions of the Gila monster. Exendins of particular interest include exendin-3 and exendin-4.
  • exendins and exendin analogs for use in the methods described herein may optionally be amidated, and may also be in an acid form, pharmaceutically acceptable salt form, or any other physiologically active form of the molecule.
  • Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2 (SEQ ID NO:1)) is a peptide found in the saliva of the Gila monster, Heloderma suspectum ; and exendin-3 (HSDGTFTSDLSKQMEEEAVRLFIEWLKNGG PSSGAPPPS-NH 2 (SEQ ID NO:2)) is a peptide found in the saliva of the beaded lizard, Heloderma horridum. Exendins have some amino acid sequence similarity to some members of the glucagon-like peptide (GLP) family.
  • GLP glucagon-like peptide
  • exendin-4 has about 53% sequence identity with glucagon-like peptide-1(GLP-1)(7-37) (HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO:22)).
  • exendin-4 is transcribed from a distinct gene, not the Gila monster homolog of the mammalian proglucagon gene from which GLP-1 is expressed.
  • exendin-4 is not an analog of GLP-1 (7-37) because the structure of synthetic exendin-4 peptide was not created by sequential modification of the structure of GLP-1. Nielsen et al, Current Opinion in Investigational Drugs, 4(4):401-405 (2003 ).
  • Synthetic exendin-4 also known as exenatide
  • BYETTA® is commercially available as BYETTA® (Amylin Pharmaceuticals, Inc. and Eli Lilly and Company).
  • BYETTA® contains exenatide, a preservative (e.g., metacresol), a tonicity-adjusting agent (e.g., mannitol), and a buffer (e.g., an acetate buffer).
  • a preservative e.g., metacresol
  • a tonicity-adjusting agent e.g., mannitol
  • a buffer e.g., an acetate buffer
  • This once weekly formulation comprises exenatide and biodegradable polymeric (e.g., poly(lactide-co-glycolide)) microspheres, and is referred to herein as EQW or BYDUREONTM (Amylin Pharmaceuticals, Inc., Eli Lilly and Company, Alkermes, Inc.).
  • EQW poly(lactide-co-glycolide)
  • Exendin analog refers to peptides or other compounds which elicit a biological activity of an exendin reference peptide, preferably having a potency equal to or better than the exendin reference peptide (e.g., exendin-4), or within five orders of magnitude (plus or minus) of potency compared to the exendin reference peptide, when evaluated by art-known measures such as receptor binding and/or competition studies as described, e.g., by Hargrove et al, Regulatory Peptides, 141:113-119 (2007 ).
  • the exendin analogs will bind in such assays with an affinity of less than 1 ⁇ M, and more preferably with an affinity of less than 3 nM, or less than 1 nM.
  • the term “exendin analog” may also be referred to as “exendin agonist”.
  • Exendin analogs also include the peptides described herein which have been chemically derivatized or altered, for example, peptides with non-natural amino acid residues (e.g., taurine, ⁇ -amino acid residues, ⁇ -amino acid residues, and D-amino acid residues), C-terminal functional group modifications, such as amides, esters, and C-terminal ketone modifications and N-terminal functional group modifications, such as acylated amines, Schiff bases, or cyclization, as found, for example, in the amino acid pyroglutamic acid. Exendin analogs may also contain other chemical moieties, such as peptide mimetics.
  • exendin analog refers to a peptide having at least 75% sequence identity to exendin-4.
  • exendin analog refers to peptides having at least 80% sequence identity to exendin-4; at least 85% sequence identity to exendin-4; at least 90% sequence identity to exendin-4; or at least 95% sequence identity to exendin-4.
  • exendin-4 SEQ ID NO:1; exendin-3 (SEQ ID NO:2); Leu 14 -exendin-4 (SEQ ID NO:3); Leu 14 ,Phe 25 -exendin-4 (SEQ ID NO:4); Leu 14 ,Ala 19 ,Phe 25 -exendin-4 (SEQ ID NO:5); exendin-4(1-30) (SEQ ID NO:6); Leu 14 -exendin-4(1-30) (SEQ ID NO:7); Leu 14 ,Phe 25 -exendin-4(1-30) (SEQ ID NO:8); Leu 14 ,Ala 19 ,Phe 25 -exendin-4(1-30) (SEQ ID NO:9); exendin4(1-28) (SEQ ID NO:10); Leu 14 -exendin-4(1-28) (SEQ ID NO:11); Leu 14 ,Phe 25 -exendin-4(1-28) (SEQ ID NO:12
  • AEEA refers to [2-(2-amino)ethoxy)]ethoxy acetic acid.
  • EDA refers to ethylenediamine.
  • MPA refers to maleimidopropionic acid.
  • the exendins and exendin analogs may optionally be amidated.
  • exendins and exendin analogs useful in the methods described herein include those described in WO 98/05351 ; WO 99/07404 ; WO 99/25727 ; WO 99/25728 ; WO 99/40788 ; WO 00/41546 ; WO 00/41548 ; WO 00/73331 ; WO 01/51078 ; WO 03/099314 ; US Patent No. 6,956,026 ; US Patent No. 6,506,724 ; US Patent No. 6,703,359 ; US Patent No. 6,858,576 ; US Patent No. 6,872,700 ; US Patent No. 6,902,744 ; US Patent No. 7,157,555 ; US Patent No. 7,223,725 ; US Patent No. 7,220,721 ; US Publication No. 2003/0036504 ; and US Publication No. 2006/0094652 .
  • GLP-1(7-37) analogs refers to peptides or other compounds which elicit a biological activity similar to that of GLP-1(7-37), when evaluated by art-known measures such as receptor binding assays or in vivo blood glucose assays as described, e.g., by Hargrove et al, Regulatory Peptides, 141:113-119 (2007 ).
  • GLP-1(7-37) analog refers to a peptide that has an amino acid sequence with 1, 2, 3, 4, 5, 6, 7 or 8 amino acid substitutions, insertions, deletions, or a combination of two or more thereof, when compared to the amino acid sequence of GLP-1(7-37).
  • the GLP-1(7-37) analog is GLP-1(7-36)-NH 2 .
  • GLP-1(7-37) analogs include the amidated forms, the acid form, the pharmaceutically acceptable salt form, and any other physiologically active form of the molecule.
  • GLP-1(7-37) refers to a peptide having at least 75% sequence identity to GLP-1(7-37).
  • GLP-1(7-37) analog refers to peptides having at least 80% sequence identity to GLP-1(7-37); at least 85% sequence identity to GLP-1(7-37); at least 90% sequence identity to GLP-1(7-37); or at least 95% sequence identity to GLP-1(7-37).
  • GLP-1(7-37) and GLP-1(7-37) analogs include GLP-1(7-37) (SEQ ID NO:22); GLP-1(7-36) )-NH 2 (SEQ ID NO:23); liraglutide (VICTOZA® from Novo Nordisk); albiglutide (SYNCRIA® from GlaxoSmithKline); taspoglutide (Hoffman La-Roche); LY2189265 (Eli Lilly and Company); LY2428757 (Eli Lilly and Company); desamino-His 7 ,Arg 26 ,Lys 34 (N ⁇ -( ⁇ -Glu(N- ⁇ -hexadecanoyl)))-GLP-1(7-37); desamino-His 7 ,Arg 26 ,Lys 34 (N ⁇ -octanoyl)-GLP-1(7-37); Arg 26,34 Lys 38 (N ⁇ -( ⁇ -carboxypenta
  • the GLP-1(7-37) or GLP-1(7-37) analogs are covalently linked (directly or by a linking group) to an Fc portion of an immunoglobulin (e.g., IgG, IgE, IgG, and the like).
  • an immunoglobulin e.g., IgG, IgE, IgG, and the like.
  • any one of SEQ ID NOs:25-40 may be covalently linked to the Fc portion of an immunoglobulin comprising the sequence of: AESKYGPPCPPCPAPXaa 16 Xaa 17 Xaa 18 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFXaa 80 STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKG QPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGXaa 230 ; wherein Xaa 16 is P or E; Xaa 17 is F, V or A; Xaa 18 is L, E or A; Xaa 80 is N or A; and Xaa 230 is K
  • the linking group may be any chemical moiety (e.g., amino acids and/or chemical groups).
  • the linking group is (-GGGGS-) x (SEQ ID NO:42) where x is 1, 2, 3, 4, 5 or 6; preferably 2, 3 or 4; more preferably 3.
  • the GLP-1(7-37) analog covalently linked to the Fc portion of an immunoglobulin comprises the amino acid sequence: HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGSGGGGSA ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQ FNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQ KSLSLSLG (SEQ ID NO:43).
  • GLP-1(7-37) or GLP-1(7-37) analog may be covalently linked (directly or through a linking group) to one or two polyethylene glycol molecules.
  • a GLP-1(7-37) analog may comprise the amino acid sequence: HXaa 8 EGTFTSDVS SYLEXaa 22 AAKEFIAWLXaa 33 KGGPSSGAPPPC 45 C 46 -Z, wherein Xaa 8 is: D-Ala, G, V, L, I, S or T; Xaa 22 is G, E, D or K; Xaa 33 is: V or I; and Z is OH or NH 2 , (SEQ ID NO:44), and, optionally, wherein (i) one polyethylene glycol moiety is covalently attached to C 45 , (ii) one polyethylene glycol moiety is covalently attached to C 46 , or (iii) one polyethylene glycol moiety is attached to C 45 and one polyethylene glycol moiety is attached
  • the GLP-1(7-37) analog is HVEGTFTSDVSSYLEEQAAKEFIAWLIKGGPSSGAPPPC 45 C 46 -N-H 2 (SEQ ID NO:45) and, optionally, wherein (i) one polyethylene glycol moiety is covalently attached to C 45 , (ii) one polyethylene glycol moiety is covalently attached to C 46 , or (iii) one polyethylene glycol moiety is attached to C 45 and one polyethylene glycol moiety is attached to C 46 .
  • GLP-1 receptor agonist compounds may be prepared by processes well known in the art, e.g., peptide purification as described in Eng et al, J. Biol. Chem., 265:20259-62 (1990 ); standard solid-phase peptide synthesis techniques as described in Raufman et al, J. Biol. Chem., 267:21432-37 (1992 ); recombinant DNA techniques as described in Sambrook et al, Molecular Cloning: A Laboratory Manual, 2d Ed., Cold Spring Harbor (1989 ); and the like.
  • the disclosure also provides pharmaceutical compositions comprising the GLP-1 receptor agonist compounds described herein and a pharmaceutically acceptable carrier.
  • the GLP-1 receptor agonist compounds can be present in the pharmaceutical composition in a therapeutically effective amount and can be present in an amount to provide a minimum blood plasma level of the GLP-1 receptor agonist compound necessary for therapeutic efficacy.
  • Such pharmaceutical compositions are known in the art and described, e.g., in US Patent No. 7,521,423 ; US Patent No. 7,456,254 ; WO 2000/037098 ; WO 2005/021022 ; WO 2005/102293 ; WO 2006/068910 ; WO 2006/125763 ; WO 2009/068910 ; and US Publication No 2004/0106547 .
  • compositions containing the GLP-1 receptor agonist compounds described herein are provided for peripheral administration, such as parenteral (e.g., subcutaneous, intravenous, intramuscular), a continuous infusion (e.g., intravenous drip, intravenous bolus, intravenous infusion), topical, nasal, or oral administration.
  • parenteral e.g., subcutaneous, intravenous, intramuscular
  • continuous infusion e.g., intravenous drip, intravenous bolus, intravenous infusion
  • topical e.g., nasal, or oral administration.
  • suitable pharmaceutically acceptable carriers and their formulation are described in standard formulation treatises, such as Remington's Pharmaceutical Sciences by Martin; and Wang et al, Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42:2S (1988 ).
  • the GLP-1 receptor agonist compounds described herein can be provided in parenteral compositions for injection or infusion. They can, for example, be suspended in water; an inert oil, such as a vegetable oil (e.g., sesame, peanut, olive oil, and the like); or other pharmaceutically acceptable carrier. In one embodiment, the compounds are suspended in an aqueous carrier, for example, in an isotonic buffer solution at a pH of about 3.0 to 8.0, or about 3.0 to 5.0.
  • the compositions may be sterilized by conventional sterilization techniques or may be sterile filtered.
  • the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH buffering agents.
  • Useful buffers include for example, acetic acid buffers.
  • a form of repository or "depot” slow release preparation may be used so that therapeutically effective amounts of the preparation are delivered into the bloodstream over many hours or days following subcutaneous injection, transdermal injection or other delivery method.
  • the desired isotonicity may be accomplished using sodium chloride or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol, polyols (such as mannitol and sorbitol), or other inorganic or organic solutes.
  • the formulation may comprise (i) the GLP-1 receptor agonist compound, (2) sterile water, and, optionally (3) sodium chloride, dextrose, or a combination thereof.
  • Carriers or excipients can also be used to facilitate administration of the GLP-1 receptor agonist compounds.
  • carriers and excipients include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents.
  • the GLP-1 receptor agonist compounds can also be formulated as pharmaceutically acceptable salts (e.g., acid addition salts) and/or complexes thereof.
  • Pharmaceutically acceptable salts are non-toxic salts at the concentration at which they are administered.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid.
  • acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid.
  • Such salts may be prepared by, for example, reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the ions of an existing salt for another ion on a suitable ion exchange resin.
  • GLP-1 receptor agonist compounds are described in US Patent No. 7,521,423 , US Patent No. 7,456,254 ; US Publication No 2004/0106547 , WO 2006/068910 , and WO 2006/125763 .
  • the therapeutically effective amount of the GLP-1 receptor agonist compounds described herein for use in the methods described herein will typically be from about 0.01 ⁇ g to about 5 mg; about 0.1 ⁇ g to about 2.5 mg; about 1 ⁇ g to about 1 mg; about 1 ⁇ g to about 50 ⁇ g; or about 1 ⁇ g to about 25 ⁇ g.
  • the therapeutically effective amount of the GLP-1 receptor agonist compounds may be from about 0.001 ⁇ g to about 100 ⁇ g based on the weight of a 70 kg patient; or from about 0.01 ⁇ g to about 50 ⁇ g based on the weight of a 70 kg patient.
  • These therapeutically effective doses may be administered once/day, twice/day, thrice/day, once/week, biweekly, or once/month, depending on the formulation.
  • the exact dose to be administered is determined, for example, by the formulation, such as an immediate release formulation or an extended release formulation.
  • the dosage may be increased from about 5-fold to about 10-fold.
  • the GLP-1 receptor agonist compound can be administered with (e.g., as separate compositions or in the same composition) an effective amount of an amylin, an amylin analog (e.g., davalintide), GIP, a GIP analog, PYY, a PYY analog, leptin, a leptin analog (e.g., metreleptin), or a combination of two or more thereof.
  • an effective amount of these compounds are known in the art or can be determined by the skilled artisan based on the knowledge in the art and the teachings herein.
  • the example is for purposes of illustration only.
  • BYETTA® Ananatide; Amylin Pharmaceuticals, Inc. and Eli Lilly and Company
  • An early assessment will be performed after 2 weeks of treatment under both conditions.
  • the baseline study will include assessment of presence and severity of obstructive sleep apnea.
  • the one week home studies will include recordings of habitual sleep duration and quality by wrist actigraphy and sleep logs, in addition to 3 days of meal logs.
  • Each second inpatient study will involve controlled caloric intake (matching the patient's daily requirements), continuous monitoring of interstitial glucose, two nights of polysomnography, and a 24 hour period of blood sampling at frequent intervals.
  • a fasting blood sample will be drawn for the measurment of CRP, HbA1c, lipids, Apolipoproetin B, and adiponectin levels.
  • the levels of plasma glucose, insulin, C-peptide, free fatty acids, leptin, ghrelin, PYY, melatonin, and catecholamines will be determined on the sample collected during 24 hour blood sampling. Additional measurements will include the 24 hour profile of heart rate variability and blood pressure, and frequent administration of scales to assess hunger, appetite, nausea, and daytime sleepiness.
  • Tissue samples will be digested collagenase to isolate adipocytes. Insulin sensitivity will be determined by incubating the cells with increasing concentrations of insulin (0-10 nM). Cells will be stimulated for 10 minutes and analyzed by phospho-specific immunoblotting or for 45 minutes pluse 14C-glucose to measure lipogenesis. Alternatively, samples will be cultured in vitro as tissue chunks for analysis of oscillation of circadian gene expression over a 2 day period. Cells will be harvested periodically and gene expression determined by quantitative real time PCR.
  • the early assessment at 2 weeks after starting treatment will include a one week home study, discussed above, and a one day inpatient study with PSG to assess early effects of exenatide on sleep, CGMS, assessments of hunger, appetite, nausea, daytime sleepiness, 24 hour profile of heart rate variability and blood pressure, fasting blood samples for CRP, lipids, ApoB, and adiponectin.
  • the primary study endpoints are (i) minutes of non-REM sleep; (ii) total amount of EEG slow-wave activity; (iii) habitual sleep duration and quality; and (iv) AHI, a validated marker of the severity of obstructive sleep apnea.
  • the second study enpoints include (i) glucose control as estimated by mean daytime, nighttime and 24 hour levels and mean peak post-prandial levels of interstitial glucose from 3 days of continuous blood glucose monitoring (CGMS) as well as HA1c; (ii) insulin sensitivity, as estimated by the fasting HOMA index, and insulin signaling directly measured in primary adipocytes using phosphospecific immunoblotting and metabolic assays; (iii) levels of hormones involved in the neuroendocrine control of appetite, including leptin, ghrelin and PYY; (iv) subjective hunger and appetite; (v) phase relationship between melatonin onset (marker of central circadian rhythmicity) and nocturnal peak of leptin profile (marker of peripheral rhythm); and (vi) rhythm of circadian gene expression in primary adipocytes.
  • CGMS continuous blood glucose monitoring

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Description

    Field
  • The description is directed to the field of medicine, more particularly, to sleep.
    • Background
  • Obstructive sleep apnea is caused by a blockage of the airway, which usually occurs when the soft tissue in the throat collapses and closes during sleep. The blockage can occur in a portion of the pharyngeal lumen and may include obstructions formed by the collapse of the tongue against the posterior wall of the pharynx, the collapse of the lateral pharyngeal walls, and the combined collapse of the tongue with impingement of the soft palate, particularly the posterior portion of the soft palate including the uvula. During each apnea event, the brain briefly arouses the sufferer in order to initiate the resumption of breathing. This type of sleep, however, is extremely fragmented and of poor quality.
  • According to the National Institutes of Health, obstructive sleep apnea affects more than twelve million Americans. Obstructive sleep apnea may result in high blood pressure, cardiovascular disease, weight gain, impotency, headaches, and memory problems if it is not treated. Despite the seriousness of obstructive sleep apnea, a general lack of awareness among the public and healthcare professionals results in the vast majority of obstructive sleep apnea sufferers remaining undiagnosed and untreated.
  • Many devices have been developed to treat obstructive sleep apnea; however, the devices can be uncomfortable for the patients. There exists a need in the art to identify therapeutic agents that can be used to enhance the quality of sleep and treat sleep apnea without causing patient discomfort. The present disclosure is directed to these, as well as other, important ends.
    • Summary
  • Provided herein are compounds and compositions for use in the treatment of obstructive sleep apnea in patients in need thereof by administering to the patients therapeutically effective amounts of GLP-1 receptor agonist compounds to treat obstructive sleep apnea. The treatment of obstructive sleep apnea includes treatment for reducing the severity of obstructive sleep apnea.
  • In some instances, obstructive sleep apnea may be treated by administering BYETTA® (exenatide; Amylin Pharmaceuticals, Inc., San Diego, CA, and Eli Lilly and Co., Indianapolis, IN) to the patient. BYETTA® is a pharmaceutical composition that generally comprises a GLP-1 receptor agonist compound (e.g., exenatide), a preservative (e.g., metacresol), a tonicity-adjusting agent (e.g., mannitol), and a buffer (e.g., an acetate buffer).
  • In some instances, obstructive sleep apnea may be treated by administering BYDUREON™ or exenatide once weekly (EQW) (Amylin Pharmaceuticals, Inc., Eli Lilly and Company, Alkermes, Inc.) to the patient. Exenatide once weekly is a pharmaceutical composition that comprises biodegradable microspheres (e.g., poly(lactide-co-glycolide) microspheres) and exenatide. Exenatide once weekly is described, for example, in WO 2007/024700 .
  • For the invention described herein, the patient may be a mammal, such as a human. Conditions such as obstructive sleep apnea are usually more common in diabetic and/or obese patients, such that the patient being treatedis more likely to be diabetic, obese, or diabetic and obese.
    • Detailed Description
  • The description relates to GLP-1 receptor agonist compounds as defined in the claims for use to treat obstructive sleep apnea in patients in need thereof. The GLP-1 receptor agonist compounds are administered to patients in therapeutically effective amounts. The patient may be a mammal, such as a human. The description relates to pharmaceutical compositions comprising GLP-1 receptor agonist compounds for use to treat obstructive sleep apnea in patients in need thereof. The pharmaceutical compositions comprise therapeutically effective amounts of the GLP-1 receptor agonist compounds. The compositions may be immediate release (e.g., administered qid, bid, tid) or extended release (e.g., administered QW or once a month). The patient may be a mammal, such as a human.
  • In one embodiment, the description relates to GLP-1 receptor agonist compounds to treat obstructive sleep apnea by administering therapeutically effective amounts to patients in need thereof. A patient with obstructive sleep apnea stops breathing numerous times, for varying amounts of time, during sleep. Methods for treating obstructive sleep apnea include reducing the number of times a patient stops breathing during the night and/or reducing the length of time a patient stops breathing. "Reducing" includes eliminating the symptoms of obstructive sleep apnea.
  • The present invention provides a GLP-1 receptor agonist compound or a pharmaceutical composition comprising the GLP-1 receptor agonist compound for use in the treatment of obstructive sleep apnea in a patient in need thereof, said treatment comprising peripherally administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition to treat the obstructive sleep apnea, wherein the GLP-1 receptor agonist compound is a GLP-1(7-37) analog ("GLP1(7-37)" disclosed as SEQ ID NO: 22); exendin-4 (SEQ ID NO:1); exendin-3 (SEQ ID NO:2); Leu14-exendin-4 (SEQ ID NO:3); Leu14,Phe25-exendin-4 (SEQ ID NO:4); Leu14,Ala19,Phe25-exendin-4 (SEQ ID NO:5); exendin-4(1-30) (SEQ ID NO:6); Leu14-exendin-4(1-30) (SEQ ID NO:7); Leu14,Phe25-exendin-4(1-30) (SEQ ID NO:8); Leu14,Ala19,Phe21-exendin-4(1-30) (SEQ ID NO:9); exendin-4(1-28) (SEQ ID NO:10); Leu14-exendin-4(1-28) (SEQ ID NO:11); Leu14,Phe25-exendin-4(1-28) (SEQ ID NO:12); Leu14Ala19,Phe25-exendin-4 (1-28) (SEQ ID NO:13); Leu14,Lys17,20,Ala19,Glu21,Phe25,Gln28-exendin-4 (SEQ ID NO:14); Leu14,Lys17,20,Ala19,Glu21,Gln28-exendin-4 (SEQ ID NO:15); octylGly14,Gln28-exendin-4 (SEQ ID NO:16); Leu14,Gln28,octylGly34-exendin-4 (SEQ ID NO:17); Phe4,Leu14,Gln28,Lys33,Glu34, Ile35,36,Ser37-exendin-4(1-37) (SEQ ID NO:18); Phe4,Leu14,Lys17,20,Ala19,Glu28,Gln28-exendin-4 (SEQ ID NO:19); Val11,Ile13,Leu14,Ala16,Lys21,Phe25-exendin-4 (SEQ ID NO:20); exendin-4-Lys40 (SEQ ID NO:21); lixisenatide; CJC-1134; [Nε-(17-carboxyheptadecanoic acid)Lys20]exendin-4-NH2; [Nε-(17-carboxyhepta-decanoyl)Lys32]exendin-4-NH2; [desamino-His1,Nε-(17-carboxyheptadecanoyl)Lys20]exendin-4-NH2; [Arg12,27,NLe14,Nε-(17-carboxy-heptadecanoyl)Lys32]exendin-4-NH2; [Nε-(19-carboxy-nonadecanoylamino)Lys20]-exendin-4-NH2; [Nε-(15-carboxypentadecanoylamino)Lys20]-exendin-4-NH2; [Nε-(13-carboxytridecanoylamino)Lys20]exendin-4-NH2; [Nε-(11-carboxy-undecanoyl-amino)Lys20]exendin-4-NH2; exendin-4-Lys40(ε-MPA)-NH2; exendin-4-Lys40(ε-AEEA-AEEA-MPA)-NH2; exendin-4-Lys40(ε-AEEA-MPA)-NH2; exendin-4-Lys40(ε-MPA)-albumin; exendin-4-Lys40(ε-AEEA-AEEA-MPA)-albumin; exendin-4-Lys40(ε-AEEA-MPA)-albumin; or SEQ ID NO:43.
  • Obstructive sleep apnea may be classified by the Apnea-Hypopnea Index (AH1) which measures the total number of episodes of apnea and hypopnea occurring during sleep divided by the hours of sleep time. The AHI classifies sleep apnea as normal (i.e., less than 5 pauses in breathing lasting more than 10 seconds): mild (i.e., 5-15 pauses in breathing lasting more than 10 seconds); moderate (i.e., 15-30 pauses in breathing lasting more than 10 second); or severe (i.e., more than 30 pauses in breathing lasting more than 10 seconds). The treatment of sleep apnea described herein includes reducing the severity of obstructive sleep apnea based on the AHI. In one embodiment, the invention described herein reduces the patient's AHI from severe to moderate; or from severe to mild; or from severe to normal. In one embodiment, the invention described herein reduces the patient's AHI from moderate to mild, or from moderate to normal. In one embodiment, the methods described herein reduce the patient's AHI from mild to normal.
  • A "GLP-1 receptor agonist compound" refers to compounds having GLP-1 receptor activity. Such compounds are exendins, exendin analogs, and GLP-1(7-37) analogs.
  • The term "exendin" includes naturally occurring (or synthetic versions of naturally occurring) exendin peptides that are found in the salivary secretions of the Gila monster. Exendins of particular interest include exendin-3 and exendin-4. The exendins and exendin analogs for use in the methods described herein may optionally be amidated, and may also be in an acid form, pharmaceutically acceptable salt form, or any other physiologically active form of the molecule.
  • Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (SEQ ID NO:1)) is a peptide found in the saliva of the Gila monster, Heloderma suspectum; and exendin-3 (HSDGTFTSDLSKQMEEEAVRLFIEWLKNGG PSSGAPPPS-NH2 (SEQ ID NO:2)) is a peptide found in the saliva of the beaded lizard, Heloderma horridum. Exendins have some amino acid sequence similarity to some members of the glucagon-like peptide (GLP) family. For example, exendin-4 has about 53% sequence identity with glucagon-like peptide-1(GLP-1)(7-37) (HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO:22)). However, exendin-4 is transcribed from a distinct gene, not the Gila monster homolog of the mammalian proglucagon gene from which GLP-1 is expressed. Additionally, exendin-4 is not an analog of GLP-1 (7-37) because the structure of synthetic exendin-4 peptide was not created by sequential modification of the structure of GLP-1. Nielsen et al, Current Opinion in Investigational Drugs, 4(4):401-405 (2003).
  • Synthetic exendin-4, also known as exenatide, is commercially available as BYETTA® (Amylin Pharmaceuticals, Inc. and Eli Lilly and Company). BYETTA® contains exenatide, a preservative (e.g., metacresol), a tonicity-adjusting agent (e.g., mannitol), and a buffer (e.g., an acetate buffer). A once weekly formulation of exenatide is currently in development and is described in WO 2005/102293 . This once weekly formulation comprises exenatide and biodegradable polymeric (e.g., poly(lactide-co-glycolide)) microspheres, and is referred to herein as EQW or BYDUREON™ (Amylin Pharmaceuticals, Inc., Eli Lilly and Company, Alkermes, Inc.).
  • "Exendin analog" refers to peptides or other compounds which elicit a biological activity of an exendin reference peptide, preferably having a potency equal to or better than the exendin reference peptide (e.g., exendin-4), or within five orders of magnitude (plus or minus) of potency compared to the exendin reference peptide, when evaluated by art-known measures such as receptor binding and/or competition studies as described, e.g., by Hargrove et al, Regulatory Peptides, 141:113-119 (2007). Preferably, the exendin analogs will bind in such assays with an affinity of less than 1 µM, and more preferably with an affinity of less than 3 nM, or less than 1 nM. The term "exendin analog" may also be referred to as "exendin agonist".
  • Exendin analogs also include the peptides described herein which have been chemically derivatized or altered, for example, peptides with non-natural amino acid residues (e.g., taurine, β-amino acid residues, γ-amino acid residues, and D-amino acid residues), C-terminal functional group modifications, such as amides, esters, and C-terminal ketone modifications and N-terminal functional group modifications, such as acylated amines, Schiff bases, or cyclization, as found, for example, in the amino acid pyroglutamic acid. Exendin analogs may also contain other chemical moieties, such as peptide mimetics.
  • In one instance the term "exendin analog" refers to a peptide having at least 75% sequence identity to exendin-4. In other instances, the term "exendin analog" refers to peptides having at least 80% sequence identity to exendin-4; at least 85% sequence identity to exendin-4; at least 90% sequence identity to exendin-4; or at least 95% sequence identity to exendin-4.
  • Exemplary exendins and exendin analogs exendin-4 (SEQ ID NO:1); exendin-3 (SEQ ID NO:2); Leu14-exendin-4 (SEQ ID NO:3); Leu14,Phe25-exendin-4 (SEQ ID NO:4); Leu14,Ala19,Phe25-exendin-4 (SEQ ID NO:5); exendin-4(1-30) (SEQ ID NO:6); Leu14-exendin-4(1-30) (SEQ ID NO:7); Leu14,Phe25-exendin-4(1-30) (SEQ ID NO:8); Leu14,Ala19,Phe25-exendin-4(1-30) (SEQ ID NO:9); exendin4(1-28) (SEQ ID NO:10); Leu14-exendin-4(1-28) (SEQ ID NO:11); Leu14,Phe25-exendin-4(1-28) (SEQ ID NO:12); Leu14,Ala19,Phe25-exendin-4 (1-28)(SEQ ID NO:13); Leu14Lys17,20,Ala19,GlU21,Phe25,Gln28-exendin-4(SEQ ID NO:14); Leu14,Lys17,20,Ala19,Glu21,Gln28-exendin-4 (SEQ ID NO:15); octylGly14,Gln28-exendin-4 (SEQ ID NO:16); Leu14,Gln28,octylGly34-exendin-4 (SEQ ID NO:17); Phe4,Leu14,Gln28,Lys33,Glu34, Ile35,36,Ser37-exendin-4(1-37) (SEQ ID NO:18); Phe4,Leu14,Lys17,20,Ala19, Glu21,Gln28-exendin-4 (SEQ ID NO:19); Val11,Il13,Leu14,Ala16,Lys21,Phe25-exendin-4 (SEQ ID NO:20); exendin-4-Lys40 (SEQ ID NO:21); lixisenatide (Sanofi-Aventis/Zealand Pharma); CJC-1134 (ConjuChem, Inc.); [Nε-(17-carboxyheptadecanoic acid)Lys20]exendin-4-NH2; [Nε-(17-carboxyheptadecanoyl)Lys32-]exendin-4-NH2; [desamino-His1,Nε-(17-carboxyheptadecanoyl)Lys20]exendin-4-NH2; [Arg12,27,NLe14,Nε-(17-carboxy-heptadecanoyl)Lys32]exendin-4-NH2; [Nε-(19-carboxy-nonadecanoylamino)Lys20]-exendin4-NH2; [Nε-(15-carboxypentadecanoylamino)Lys20]-exendin-4-NH2; [Nε-(13-carboxytridecanoylamino)Lys20exendin-4-NH2; [Nε-(11-carboxyundecanoyl-arnino)Lys20]exendin-4-NH2; excndin-4-Lys40(ε-MPA)-NH2; exendin-4-Lys40(ε-AEEA-AEEA-MPA)-NH2; exendin-4-Lys40(ε-AEEA-MPA)-NH2; exendin-4-Lys40(ε-MPA)-albumin; exendin-4-Lys40(ε-AEEA-AEEA-MPA)-albumin; exendin-4-Lys40(ε-AEEA-MPA)-albumin; and the like. AEEA refers to [2-(2-amino)ethoxy)]ethoxy acetic acid. EDA refers to ethylenediamine. MPA refers to maleimidopropionic acid. The exendins and exendin analogs may optionally be amidated.
  • Other exendins and exendin analogs useful in the methods described herein include those described in WO 98/05351 ; WO 99/07404 ; WO 99/25727 ; WO 99/25728 ; WO 99/40788 ; WO 00/41546 ; WO 00/41548 ; WO 00/73331 ; WO 01/51078 ; WO 03/099314 ; US Patent No. 6,956,026 ; US Patent No. 6,506,724 ; US Patent No. 6,703,359 ; US Patent No. 6,858,576 ; US Patent No. 6,872,700 ; US Patent No. 6,902,744 ; US Patent No. 7,157,555 ; US Patent No. 7,223,725 ; US Patent No. 7,220,721 ; US Publication No. 2003/0036504 ; and US Publication No. 2006/0094652 .
  • "GLP-1(7-37) analogs" refers to peptides or other compounds which elicit a biological activity similar to that of GLP-1(7-37), when evaluated by art-known measures such as receptor binding assays or in vivo blood glucose assays as described, e.g., by Hargrove et al, Regulatory Peptides, 141:113-119 (2007). In one instance, the term "GLP-1(7-37) analog" refers to a peptide that has an amino acid sequence with 1, 2, 3, 4, 5, 6, 7 or 8 amino acid substitutions, insertions, deletions, or a combination of two or more thereof, when compared to the amino acid sequence of GLP-1(7-37). In one instance, the GLP-1(7-37) analog is GLP-1(7-36)-NH2. GLP-1(7-37) analogs include the amidated forms, the acid form, the pharmaceutically acceptable salt form, and any other physiologically active form of the molecule.
  • In one instance, the term "GLP-1(7-37)" refers to a peptide having at least 75% sequence identity to GLP-1(7-37). In other instances, the term "GLP-1(7-37) analog" refers to peptides having at least 80% sequence identity to GLP-1(7-37); at least 85% sequence identity to GLP-1(7-37); at least 90% sequence identity to GLP-1(7-37); or at least 95% sequence identity to GLP-1(7-37).
  • Exemplary GLP-1(7-37) and GLP-1(7-37) analogs include GLP-1(7-37) (SEQ ID NO:22); GLP-1(7-36) )-NH2 (SEQ ID NO:23); liraglutide (VICTOZA® from Novo Nordisk); albiglutide (SYNCRIA® from GlaxoSmithKline); taspoglutide (Hoffman La-Roche); LY2189265 (Eli Lilly and Company); LY2428757 (Eli Lilly and Company); desamino-His7,Arg26,Lys34(Nε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37); desamino-His7,Arg26,Lys34(Nε-octanoyl)-GLP-1(7-37); Arg26,34Lys38(Nε-(ω-carboxypentadecanoyl))-GLP-1(7-38); Arg26,34,Lys36(Nε-(γ-Glu(N-α- hexadecanoyl)))-GLP-1(7-36); Aib8,35Arg26,34,Phe31-GLP-1(7-36)) (SEQ ID NO:24); HXaa8EGTFTSDVSSYLEXaa22Xaa23AAKEFIXaa30WLXaa33Xaa34G Xaa36Xaa37; wherein Xaa8 is A, V, or G; Xaa22 is G, K, or E; Xaa23 is Q or K; Xaa30 is A or E; Xaa33 is V or K; Xaa34 is K, N, or R; Xaa36 is R or G; and Xaa37 is G, H, P, or absent (SEQ NO:25); Arg34-GLP-1(7-37) (SEQ ID NO:26); Glu30-GLP-1(7-37) (SEQ ID NO:27); Lys22-GLP-1(7-37) (SEQ ID NO:28); Glyg8,26Glu22-GLP-1(7-37) (SEQ ID NO:29); Val8,Glu22,Gly36-GLP-1(7-37) (SEQ ID NO:30); Gly8,36,Glu22,Lys33,Asn34-GLP-1(7-37) (SEQ ID NO:31); Val8,Glu22,Lys33,Asn34,Gly36-GLP-1(7-37) (SEQ ID NO:32); Gly8,36,Glu22,Pro37-GLP-1(7-37) (SEQ ID NO:33); Val8,Glu22,Gly36Pro37-GLP-1(7-37) (SEQ ID NO:34); Gly8,36,Glu22,Lys33, Asn34,Pro37-GLP-1(7-37) (SEQ IDNO:35); Val8,Glu22,Lys33,Asn34,Gly36,Pro37-GLP-1(7-37) (SEQ ID NO:36); Gly8,36,Glu22-GLP-1(7-36) (SEQ ID NO:37); Val8,Glu22,Gly36-GLP-1(7-36) (SEQ ID NO:38); Val8,Glu22,Asn34,Gly36-GLP-1(7-36) (SEQ ID NO:39); Gly8,36,Glu22,Asn34-GLP-1 (7-36) (SEQ ID NO:40). Each of the GLP-1(7-37) and GLP-1(7-37) analogs may optionally be amidated.
  • In one instance, the GLP-1(7-37) or GLP-1(7-37) analogs are covalently linked (directly or by a linking group) to an Fc portion of an immunoglobulin (e.g., IgG, IgE, IgG, and the like). For example, any one of SEQ ID NOs:25-40 may be covalently linked to the Fc portion of an immunoglobulin comprising the sequence of: AESKYGPPCPPCPAPXaa16 Xaa17Xaa18GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFXaa80STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKG QPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGXaa230; wherein Xaa16 is P or E; Xaa17 is F, V or A; Xaa18 is L, E or A; Xaa80 is N or A; and Xaa230 is K or absent (SEQ ID NO:41). The linking group may be any chemical moiety (e.g., amino acids and/or chemical groups). In one instance, the linking group is (-GGGGS-)x (SEQ ID NO:42) where x is 1, 2, 3, 4, 5 or 6; preferably 2, 3 or 4; more preferably 3. In one instance, the GLP-1(7-37) analog covalently linked to the Fc portion of an immunoglobulin comprises the amino acid sequence: HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGSGGGGSA ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQ FNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQ KSLSLSLG (SEQ ID NO:43).
  • In another instance, the GLP-1(7-37) or GLP-1(7-37) analog may be covalently linked (directly or through a linking group) to one or two polyethylene glycol molecules. For example, a GLP-1(7-37) analog may comprise the amino acid sequence: HXaa8EGTFTSDVS SYLEXaa22AAKEFIAWLXaa33KGGPSSGAPPPC45C46-Z, wherein Xaa8 is: D-Ala, G, V, L, I, S or T; Xaa22 is G, E, D or K; Xaa33 is: V or I; and Z is OH or NH2, (SEQ ID NO:44), and, optionally, wherein (i) one polyethylene glycol moiety is covalently attached to C45, (ii) one polyethylene glycol moiety is covalently attached to C46, or (iii) one polyethylene glycol moiety is attached to C45 and one polyethylene glycol moiety is attached to C46. In one instance, the GLP-1(7-37) analog is HVEGTFTSDVSSYLEEQAAKEFIAWLIKGGPSSGAPPPC45C46-N-H2 (SEQ ID NO:45) and, optionally, wherein (i) one polyethylene glycol moiety is covalently attached to C45, (ii) one polyethylene glycol moiety is covalently attached to C46, or (iii) one polyethylene glycol moiety is attached to C45 and one polyethylene glycol moiety is attached to C46.
  • GLP-1 receptor agonist compounds may be prepared by processes well known in the art, e.g., peptide purification as described in Eng et al, J. Biol. Chem., 265:20259-62 (1990); standard solid-phase peptide synthesis techniques as described in Raufman et al, J. Biol. Chem., 267:21432-37 (1992); recombinant DNA techniques as described in Sambrook et al, Molecular Cloning: A Laboratory Manual, 2d Ed., Cold Spring Harbor (1989); and the like.
  • The disclosure also provides pharmaceutical compositions comprising the GLP-1 receptor agonist compounds described herein and a pharmaceutically acceptable carrier. The GLP-1 receptor agonist compounds can be present in the pharmaceutical composition in a therapeutically effective amount and can be present in an amount to provide a minimum blood plasma level of the GLP-1 receptor agonist compound necessary for therapeutic efficacy. Such pharmaceutical compositions are known in the art and described, e.g., in US Patent No. 7,521,423 ; US Patent No. 7,456,254 ; WO 2000/037098 ; WO 2005/021022 ; WO 2005/102293 ; WO 2006/068910 ; WO 2006/125763 ; WO 2009/068910 ; and US Publication No 2004/0106547 .
  • Pharmaceutical compositions containing the GLP-1 receptor agonist compounds described herein are provided for peripheral administration, such as parenteral (e.g., subcutaneous, intravenous, intramuscular), a continuous infusion (e.g., intravenous drip, intravenous bolus, intravenous infusion), topical, nasal, or oral administration. Suitable pharmaceutically acceptable carriers and their formulation are described in standard formulation treatises, such as Remington's Pharmaceutical Sciences by Martin; and Wang et al, Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42:2S (1988).
  • The GLP-1 receptor agonist compounds described herein can be provided in parenteral compositions for injection or infusion. They can, for example, be suspended in water; an inert oil, such as a vegetable oil (e.g., sesame, peanut, olive oil, and the like); or other pharmaceutically acceptable carrier. In one embodiment, the compounds are suspended in an aqueous carrier, for example, in an isotonic buffer solution at a pH of about 3.0 to 8.0, or about 3.0 to 5.0. The compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH buffering agents. Useful buffers include for example, acetic acid buffers. A form of repository or "depot" slow release preparation may be used so that therapeutically effective amounts of the preparation are delivered into the bloodstream over many hours or days following subcutaneous injection, transdermal injection or other delivery method. The desired isotonicity may be accomplished using sodium chloride or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol, polyols (such as mannitol and sorbitol), or other inorganic or organic solutes. In one instance for intravenous infusion, the formulation may comprise (i) the GLP-1 receptor agonist compound, (2) sterile water, and, optionally (3) sodium chloride, dextrose, or a combination thereof.
  • Carriers or excipients can also be used to facilitate administration of the GLP-1 receptor agonist compounds. Examples of carriers and excipients include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents.
  • The GLP-1 receptor agonist compounds can also be formulated as pharmaceutically acceptable salts (e.g., acid addition salts) and/or complexes thereof. Pharmaceutically acceptable salts are non-toxic salts at the concentration at which they are administered. Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid. Such salts may be prepared by, for example, reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the ions of an existing salt for another ion on a suitable ion exchange resin.
  • Exemplary pharmaceutical formulations of GLP-1 receptor agonist compounds are described in US Patent No. 7,521,423 , US Patent No. 7,456,254 ; US Publication No 2004/0106547 , WO 2006/068910 , and WO 2006/125763 .
  • The therapeutically effective amount of the GLP-1 receptor agonist compounds described herein for use in the methods described herein will typically be from about 0.01 µg to about 5 mg; about 0.1 µg to about 2.5 mg; about 1 µg to about 1 mg; about 1 µg to about 50 µg; or about 1 µg to about 25 µg. Alternatively, the therapeutically effective amount of the GLP-1 receptor agonist compounds may be from about 0.001 µg to about 100 µg based on the weight of a 70 kg patient; or from about 0.01 µg to about 50 µg based on the weight of a 70 kg patient. These therapeutically effective doses may be administered once/day, twice/day, thrice/day, once/week, biweekly, or once/month, depending on the formulation. The exact dose to be administered is determined, for example, by the formulation, such as an immediate release formulation or an extended release formulation. For transdermal, nasal or oral dosage forms, the dosage may be increased from about 5-fold to about 10-fold.
  • In other instances of the invention described herein, the GLP-1 receptor agonist compound can be administered with (e.g., as separate compositions or in the same composition) an effective amount of an amylin, an amylin analog (e.g., davalintide), GIP, a GIP analog, PYY, a PYY analog, leptin, a leptin analog (e.g., metreleptin), or a combination of two or more thereof. Therapeutically effective amounts of these compounds are known in the art or can be determined by the skilled artisan based on the knowledge in the art and the teachings herein.
    • Example
  • The example is for purposes of illustration only.
  • Thirty human patients with type 2 diabetes will take part in a six week, randomized, double-blind, placebo-controlled, parallel group study to determine the impact of exenatide on sleep and circadian function. The study will evaluate, e.g., minutes of NREM sleep; total amount of EEG slow-wave activity; habitual sleep duration and quality; and apnea-hypopnea index (AHI), a validated marker of the severity of obstructive sleep apnea.
  • Patients will be studied prior to randomization (baseline) and at the end of six weeks of treatment with twice daily subcutaneous injections of BYETTA® (exenatide; Amylin Pharmaceuticals, Inc. and Eli Lilly and Company) (5 µg for the first two week, and then 10 µg for the next four weeks) or placebo. An early assessment will be performed after 2 weeks of treatment under both conditions. The baseline study will include assessment of presence and severity of obstructive sleep apnea. The one week home studies will include recordings of habitual sleep duration and quality by wrist actigraphy and sleep logs, in addition to 3 days of meal logs.
  • Each second inpatient study will involve controlled caloric intake (matching the patient's daily requirements), continuous monitoring of interstitial glucose, two nights of polysomnography, and a 24 hour period of blood sampling at frequent intervals. A fasting blood sample will be drawn for the measurment of CRP, HbA1c, lipids, Apolipoproetin B, and adiponectin levels. The levels of plasma glucose, insulin, C-peptide, free fatty acids, leptin, ghrelin, PYY, melatonin, and catecholamines will be determined on the sample collected during 24 hour blood sampling. Additional measurements will include the 24 hour profile of heart rate variability and blood pressure, and frequent administration of scales to assess hunger, appetite, nausea, and daytime sleepiness. A biopsy of abdominal fat from the peri-umbilical region will be obtained. Tissue samples will be digested collagenase to isolate adipocytes. Insulin sensitivity will be determined by incubating the cells with increasing concentrations of insulin (0-10 nM). Cells will be stimulated for 10 minutes and analyzed by phospho-specific immunoblotting or for 45 minutes pluse 14C-glucose to measure lipogenesis. Alternatively, samples will be cultured in vitro as tissue chunks for analysis of oscillation of circadian gene expression over a 2 day period. Cells will be harvested periodically and gene expression determined by quantitative real time PCR.
  • The early assessment at 2 weeks after starting treatment will include a one week home study, discussed above, and a one day inpatient study with PSG to assess early effects of exenatide on sleep, CGMS, assessments of hunger, appetite, nausea, daytime sleepiness, 24 hour profile of heart rate variability and blood pressure, fasting blood samples for CRP, lipids, ApoB, and adiponectin.
  • The primary study endpoints are (i) minutes of non-REM sleep; (ii) total amount of EEG slow-wave activity; (iii) habitual sleep duration and quality; and (iv) AHI, a validated marker of the severity of obstructive sleep apnea. The second study enpoints include (i) glucose control as estimated by mean daytime, nighttime and 24 hour levels and mean peak post-prandial levels of interstitial glucose from 3 days of continuous blood glucose monitoring (CGMS) as well as HA1c; (ii) insulin sensitivity, as estimated by the fasting HOMA index, and insulin signaling directly measured in primary adipocytes using phosphospecific immunoblotting and metabolic assays; (iii) levels of hormones involved in the neuroendocrine control of appetite, including leptin, ghrelin and PYY; (iv) subjective hunger and appetite; (v) phase relationship between melatonin onset (marker of central circadian rhythmicity) and nocturnal peak of leptin profile (marker of peripheral rhythm); and (vi) rhythm of circadian gene expression in primary adipocytes.
    • SEQUENCE LISTING
    • <110> AMYLIN PHARMACEUTICALS, INC. ELI LILLY AND COMPANY
    • <120> GLP-1 RECEPTOR AGONIST COMPOUNDS FOR OBSTRUCTIVE SLEEP APNEA
    • <130> N.116849
    • <140> EP 10828932.3
      <141> 2010-10-28
    • <150> US 61/257,603
      <151> 2009-11-03
    • <160> 45
    • <170> PatentIn version 3.5
    • <210> 1
      <211> 39
      <212> PRT
      <213> Heloderma suspectum
    • <220>
      <221> MOD_RES
      <222> (39)..(39)
      <223> AMIDATION (C-term amidated)
    • <400> 1
      Figure imgb0001
    • <210> 2
      <211> 39
      <212> PRT
      <213> Heloderma horridum
    • <220>
      <221> MOD_RES
      <222> (39)..(39)
      <223> AMIDATION (C-term is amidated)
    • <400> 2
      Figure imgb0002
      Figure imgb0003
    • <210> 3
      <211> 39
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (39)..(39)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 3
      Figure imgb0004
    • <210> 4
      <211> 39
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (39)..(39)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 4
      Figure imgb0005
    • <210> 5
      <211> 39
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (39)..(39)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 5
      Figure imgb0006
    • <210> 6
      <211> 30
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (30)..(30)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 6
      Figure imgb0007
    • <210> 7
      <211> 30
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (30).. (30)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 7
      Figure imgb0008
      Figure imgb0009
    • <210> 8
      <211> 30
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (30)..(30)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 8
      Figure imgb0010
    • <210> 9
      <211> 30
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (30)..(30)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 9
      Figure imgb0011
    • <210> 10
      <211> 28
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic peptide
    • <220>
      <221> MOD_RES
      <222> (28)..(28)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 10
      Figure imgb0012
    • <210> 11
      <211> 28
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic peptide
    • <220>
      <221> MOD_RES
      <222> (28)..(28)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 11
      Figure imgb0013
    • <210> 12
      <211> 28
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic peptide
    • <220>
      <221> MOD_RES
      <222> (28)..(28)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 12
      Figure imgb0014
    • <210> 13
      <211> 28
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic peptide
    • <220>
      <221> MOD_RES
      <222> (28)..(28)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 13
      Figure imgb0015
    • <210> 14
      <211> 39
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (39)..(39)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 14
      Figure imgb0016
    • <210> 15
      <211> 39
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (39)..(39)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 15
      Figure imgb0017
      Figure imgb0018
    • <210> 16
      <211> 39
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (14)..(14)
      <223> Octyl-Gly
    • <220>
      <221> MOD_RES
      <222> (39)..(39)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 16
      Figure imgb0019
    • <210> 17
      <211> 39
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (34)..(34)
      <223> Octyl-Gly
    • <220>
      <221> MOD_RES
      <222> (39)..(39)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 17
      Figure imgb0020
    • <210> 18
      <211> 37
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (37)..(37)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 18
      Figure imgb0021
    • <210> 19
      <211> 39
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (39)..(39)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 19
      Figure imgb0022
      Figure imgb0023
    • <210> 20
      <211> 39
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (39)..(39)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 20
      Figure imgb0024
    • <210> 21
      <211> 40
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (40)..(40)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 21
      Figure imgb0025
    • <210> 22
      <211> 31
      <212> PRT
      <213> Homo sapiens
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 22
      Figure imgb0026
    • <210> 23
      <211> 30
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (30)..(30)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 23
      Figure imgb0027
    • <210> 24
      <211> 30
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (2)..(2)
      <223> Aib
    • <220>
      <221> MOD_RES
      <222> (29)..(29)
      <223> Aib
    • <220>
      <221> MOD_RES
      <222> (30)..(30)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 24
      Figure imgb0028
    • <210> 25
      <211> 31
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (2)..(2)
      <223> Ala, Val, or Gly
    • <220>
      <221> MOD_RES
      <222> (16)..(16)
      <223> Gly, Lys, or Glu
    • <220>
      <221> MOD_RES
      <222> (17)..(17)
      <223> Gln or Lys
    • <220>
      <221> MOD_RES
      <222> (24)..(24)
      <223> Ala or Glu
    • <220>
      <221> MOD_RES
      <222> (27)..(27)
      <223> Val or Lys
    • <220>
      <221> MOD_RES
      <222> (28)..(28)
      <223> Lys, Asn, or Arg
    • <220>
      <221> MOD_RES
      <222> (30)..(30)
      <223> Arg or Gly
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> Gly, His, Pro, or not present
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 25
      Figure imgb0029
      Figure imgb0030
    • <210> 26
      <211> 31
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 26
      Figure imgb0031
    • <210> 27
      <211> 31
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 27
      Figure imgb0032
    • <210> 28
      <211> 31
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION(C-term may or may not be amidated)
    • <400> 28
      Figure imgb0033
    • <210> 29
      <211> 31
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 29
      Figure imgb0034
    • <210> 30
      <211> 31
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 30
      Figure imgb0035
    • <210> 31
      <211> 31
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 31
      Figure imgb0036
    • <210> 32
      <211> 31
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 32
      Figure imgb0037
    • <210> 33
      <211> 31
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 33
      Figure imgb0038
      Figure imgb0039
    • <210> 34
      <211> 31
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 34
      Figure imgb0040
    • <210> 35
      <211> 31
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 35
      Figure imgb0041
    • <210> 36
      <211> 31
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (31)..(31)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 36
      Figure imgb0042
    • <210> 37
      <211> 30
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (30)..(30)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 37
      Figure imgb0043
    • <210> 38
      <211> 30
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (30)..(30)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 38
      Figure imgb0044
    • <210> 39
      <211> 30
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (30)..(30)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 39
      Figure imgb0045
    • <210> 40
      <211> 30
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (30)..(30)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 40
      Figure imgb0046
    • <210> 41
      <211> 230
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (16)..(16)
      <223> Pro or Glu
    • <220>
      <221> MOD_RES
      <222> (17)..(17)
      <223> Phe, Val, or Ala
    • <220>
      <221> MOD_RES
      <222> (18)..(18)
      <223> Leu, Glu, or Ala
    • <220>
      <221> MOD_RES
      <222> (80)..(80)
      <223> Asn or Ala
    • <220>
      <221> MOD_RES
      <222> (230)..(230)
      <223> May or may not be present
    • <400> 41
      Figure imgb0047
      Figure imgb0048
    • <210> 42
      <211> 30
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> misc_feature
      <222> (1)..(30)
      <223> This sequence may encompass 1-6 repeating "GGGGS" subunits
    • <400> 42
      Figure imgb0049
    • <210> 43
      <211> 275
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <400> 43
      Figure imgb0050
      Figure imgb0051
    • <210> 44
      <211> 40
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (2)..(2)
      <223> D-Ala, Gly, Val, Leu, Ile, Ser, or Thr
    • <220>
      <221> MOD_RES
      <222> (16)..(16)
      <223> Gly, Glu, Asp, or Lys
    • <220>
      <221> MOD_RES
      <222> (27)..(27)
      <223> Val or Ile
    • <220>
      <221> MOD_RES
      <222> (40)..(40)
      <223> C-term OH or NH2
    • <400> 44
      Figure imgb0052
    • <210> 45
      <211> 40
      <212> PRT
      <213> Artificial Sequence
    • <220>
      <223> Description of Artificial Sequence: Synthetic polypeptide
    • <220>
      <221> MOD_RES
      <222> (40)..(40)
      <223> AMIDATION (C-term may or may not be amidated)
    • <400> 45
      Figure imgb0053

Claims (4)

  1. A GLP-1 receptor agonist compound or a pharmaceutical composition comprising a GLP-1 receptor agonist compound for use in the treatment of obstructive sleep apnea in a patient in need thereof, said treatment comprising peripherally administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition to treat the obstructive sleep apnea, wherein the GLP-1 receptor agonist compound is a GLP-1(7-37) analog ("GLP1(7-37)" disclosed as SEQ ID NO: 22); exendin-4 (SEQ ID NO:1); exendin-3 (SEQ ID NO:2); Leu14-exendin-4 (SEQ ID NO:3); Leu14,Phe25-exendin-4 (SEQ ID NO:4); Leu14,Ala19,Phe25-exendin-4 (SEQ ID NO:5); exendin-4(1-30) (SEQ ID NO:6); Leu14-exendin-4(1-30) (SEQ ID NO:7); Leu14,Phe25-exendin-4(1-30) (SEQ ID NO:8); Leu14,Ala19,Phe25-exendin-4(1-30) (SEQ ID NO:9); exendin-4(1-28) (SEQ ID NO:10); Leu14-exendin-4(1-28) (SEQ ID NO:11); Leu14,Phe25-exendin-4(1-28) (SEQ ID NO:12); Leu14,Ala19,Phe25-exendin-4 (1-28) (SEQ ID NO:13); Leu14,Lys17,20,Ala19,Glu21,Phe25,Gln28-exendin-4 (SEQ ID NO:14); Leu14,Lys17,20,Ala19,Glu21,Gln28-exendin-4 (SEQ ID NO:15); octylGly14,Gln28-exendin-4 (SEQ ID NO:16); Leu14,Gln28,octylGly34-exendin-4 (SEQ ID NO:17); Phe4,Leu14,Gln28,Lys33,Glu34, Ile35,36,Ser37-exendin-4(1-37) (SEQ ID NO:18); Phe4,Leu14,Lys17,20,Ala19,Glu28,Gln28-exendin-4 (SEQ ID NO:19); Val11,Ile13,Leu14,Ala16,Lys21,Phe25-exendin-4 (SEQ ID NO:20); exendin-4-Lys40 (SEQ ID NO:21); lixisenatide; CJC-1134; [Nε-(17-carboxyheptadecanoic acid)Lys20]exendin-4-NH2; [Nε-(17-carboxyheptadecanoyl)Lys32]exendin-4-NH2; [desamino-His1,Nε-(17-carboxyheptadecanoyl)Lys20]exendin-4-NH2; [Arg12,27,NLe14,Nε-(17-carboxy-heptadecanoyl)Lys32]exendin-4-NH2; [Nε-(19-carboxynonadecanoylamino)Lys20]-exendin-4- NH2; [N6-(15-carboxypentadecanoylamino)Lys20]-exendin-4-NH2; [Nε-(13-carboxytridecanoylamino)Lys20]exendin-4-NH2; [Nε-(11-carboxy-undecanoyl-amino)Lys20]exendin-4-NH2; exendin-4-Lys40(ε-MPA)-NH2; exendin-4-Lys40(ε-AEEA-AEEA-MPA)-NH2; exendin-4-Lys40(ε-AEEA-MPA)-NH2; exendin-4-Lys40(ε-MPA)-albumin; exendin-4-Lys40(ε-AEEA-AEEA-MPA)-albumin; exendin-4-Lys40(ε-AEEA-MPA)-albumin; or SEQ ID NO:43.
  2. The compound or pharmaceutical composition for use according to claim 1, wherein the GLP-1 receptor agonist compound is GLP-1(7-37) (SEQ ID NO:22); GLP-1(7-36) (SEQ ID NO:23); liraglutide; albiglutide; taspoglutide; LY2189265; LY2428757; desamino-His7,Arg26,Lys34(Nε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37); desamino-His7,Arg26,Lys34(Nε-octanoyl)-GLP-1(7-37); Arg26,34,Lys38(Nε-(ω-carboxypentadecanoyl))-GLP-1(7-38); Arg26,34,Lys36(Nε-(γ-Glu(N-α- hexadecanoyl)))-GLP-1(7-36); Aib8,35,Arg26,34,Phe31-GLP-1(7-36)) (SEQ ID NO:24); HXaa8EGTFTSDVSSYLEXaa22Xaa23AAKEFIXaa30WLXaa33Xaa34G Xaa36Xaa37; wherein Xaa8 is A, V, or G; Xaa22 is G, K, or E; Xaa23 is Q or K; Xaa30 is A or E; Xaa33 is V or K; Xaa34 is K, N, or R; Xaa36 is R or G; and Xaa37 is G, H, P, or absent (SEQ ID NO:25); Arg34-GLP-1(7-37) (SEQ ID NO:26); Glu30-GLP-1(7-37) (SEQ ID NO:27); Lys22-GLP-1(7-37) (SEQ ID NO:28); Gly8,36,Glu22-GLP-1(7-37) (SEQ ID NO:29); Val8,Glu22,Gly36-GLP-1(7-37) (SEQ ID NO:30); Gly8,36,Glu22,Lys33,Asn34-GLP-1(7-37) (SEQ ID NO:31); Val8,Glu22,Lys33,Asn34,Gly36-GLP-1(7-37) (SEQ ID NO:32); Gly8,36,Glu22,Pro37-GLP-1(7-37) (SEQ ID NO:33); Val8,Glu22,Gly36Pro37-GLP-1(7-37) (SEQ ID NO:34); Gly8,36,Glu22,Lys33, Asn34,Pro37-GLP-1(7-37) (SEQ ID NO:35); Val8,Glu,22,Lys33,Asn34,Gly36,Pro37-GLP-1(7-37) (SEQ ID NO:36); Gly8,36,Glu22-GLP-1(7-36) (SEQ ID NO:37); Val8,Glu22,Gly36-GLP-1(7-36) (SEQ ID NO:38); Val8,Glu22,Asn34,Gly36-GLP-1(7-36) (SEQ ID NO:39); or Gly8,36,Glu22,Asn34-GLP-1(7-36) (SEQ ID NO:40).
  3. The compound or pharmaceutical composition for use according to claim 1, wherein the GLP-1 receptor agonist compound is any one of SEQ ID NOs:25-40 covalently linked to the Fc portion of an immunoglobulin comprising the sequence of:
    Figure imgb0054
    wherein Xaa16 is P or E; Xaa17 is F, V or A; Xaa18 is L, E or A; Xaa80 is N or A; and Xaa230 is K or absent (SEQ ID NO:41).
  4. The compound or pharmaceutical composition for use according to claim 1, wherein the GLP-1 receptor agonist compound is exendin-4 (SEQ ID NO:1).
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